Navigating 'deterioration in mental state' - from recognition to response in general hospitals to satisfy 'National Standards': a discussion paper.

Background: The Australian Commission on Safety and Quality in Health Care 'National Standards' require general hospitals to have systems for clinicians to recognise and respond to patients' deteriorating mental state. The lack of an evidence-based operational definition and clear guidance challenges this requirement.

Objective: To review governance mechanisms and assessment processes for deteriorating mental state in a metropolitan general hospital and propose an organisational framework.

Discovery and Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4747, a clinical development candidate for the treatment of KRAS-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK.

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability.

Mapping quality improvement education initiatives to Standards for QUality Improvement Reporting Excellence (SQUIRE) guidelines.

Aims And Objectives: To explore the rigour of nurse-led quality improvement projects involving education, training or continuing professional development, and examine evaluation frameworks contained within.

Background: Healthcare organisations invest significantly in quality improvement in the pursuit of cost-effective, safe, evidence-based and person-centred care. Consequently, efforts to examine the success of investment in quality improvement activities are prominent, against a backdrop of rising healthcare expenditure, reforms, consumer expectations and feedback.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4625, a clinical development candidate for the treatment of KRAS positive tumors.

Empathy education in post-graduate nurses: An integrative review.

Aim: This study reviews the outcomes of programmes teaching empathy to post-graduate nurses.

Background: Nurses who are able to empathise with their patients, place themselves within a preferred position to deliver better patient outcomes. There have been substantial efforts to improve the empathy skill level of undergraduate nursing students, with success but understanding this skill level at the post graduate level is limited.

Development and effectiveness of tabletop exercises in preparing health practitioners in violence prevention management: A sequential explanatory mixed methods study.

Background: Workplace violence in healthcare remains a significant issue for healthcare professional, in terms of risk to patients and staff. One part of a workplace violence prevention and management programme is to educate staff in their response to critical events. Drawn from the disaster management literature, tabletop exercises were used in this study to simulate workplace violence and educate staff on the appropriate emergency response during a violent event.

Examining the utility of the Violence Prevention Climate scale: In a metropolitan Australian general hospital.

Aim And Objectives: To evaluate and examine the utility of the Violence Prevention Climate scale by generalist healthcare professionals.

Background: Workplace violence in general hospital settings remains a challenge for healthcare organisations. High rates of violence are still being reported towards healthcare workers, despite organisational violence prevention strategies being implemented.

The role of work in gender identity, stress and health in low-income, middle-aged African-American men.

Although progress has been made in reducing disparities in life expectancy, addressing the persistence of health inequities by race remains a high priority for public health professionals. The purpose of this research was to refine a minority stress model (MSM) by identifying previously unrecognized factors contributing to stress and chronic disease health disparities among low-income middle-aged African-American men. Using a Community-Based Participatory Research approach, we conducted semi-structured individual health interviews with 42 low-income middle-aged African-American men in a mid-size New England city.

A culturally and gender responsive stress and chronic disease prevention intervention for low/no-income African American men: The MOCHA moving forward randomized control trial protocol.

Low/no-income, African American men are disproportionally burdened by chronic disease resulting from a complex interplay of systemic, sociocultural, and individual factors. These disparities are related to poverty, racism, gender role strain, high levels of stress, low levels of physical activity, and malnutritious diet. Men of Color Health Awareness (MOCHA) is a community-driven movement to address the physical, mental, social, and spiritual needs of men of color.

Mental Capacity Assessments for COVID-19 Patients: Emergency Admissions and the CARD Approach.

The doctrine of consent (or informed consent, as it is called in North America) is built upon presumptions of mental capacity. Those presumptions must be tested according to legal rules that may be difficult to apply to COVID-19 patients during emergency presentations. We examine the principles of mental capacity and make recommendations on how to assess the capacity of COVID-19 patients to consent to emergency medical treatment.

COVID-19 and Australian Prisons: Human Rights, Risks, and Responses.

Australian prisons are overpopulated with people suffering from numerous health problems. COVID-19 presents a significant threat to prisoner health. This article examines the current regulatory responses from Australian state and territory governments to COVID-19 and a recent case which tested the human rights of prisoners during a pandemic.

Understanding Ethical and Legal Obligations in a Pandemic: A Taxonomy of "Duty" for Health Practitioners.

From the ethics perspective, "duty of care" is a difficult and contested term, fraught with misconceptions and apparent misappropriations. However, it is a term that clinicians use frequently as they navigate COVID-19, somehow core to their understanding of themselves and their obligations, but with uncertainty as to how to translate or operationalize this in the context of a pandemic. This paper explores the "duty of care" from a legal perspective, distinguishes it from broader notions of duty on professional and personal levels, and proposes a working taxonomy for practitioners to better understand the concept of "duty" in their response to COVID-19.

The misuse of "duty of care" as justification for non-consensual coercive treatment.

The duty of care concept is a common law legal principle which underpins all healthcare interactions. However, evidence within the Australian context suggests misuse of this common law principle as a justification for non-consensual coercive treatment. Misuse seems to occur particularly where patients have impaired decision-making capacity and/or refuse treatment.

Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase.

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits.

Optimization of a series of potent, selective and orally bioavailable SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRAS.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification.

Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops.

Mind the gaps: identifying opportunities in mental health assessment and mental health certificate completion in rural and remote NSW, Australia.

Objective: This study aimed to examine the quality of mental health certificate (MHC) completion in rural and remote New South Wales, to include the determination of those identified as mentally ill or mentally disordered, and subsequent processes thereafter.

Methods: MHCs were collected from April 2016 to March 2017. A de-identified review was undertaken and audited for completion of mandatory criteria.

Participant Engagement and Ethical Digital Storytelling: The MOCHA Moving Forward Study.

African-American men continue to bear a disproportionate share of the burden of health disparities, in general, and chronic diseases, in particular. The Men of Color Health Awareness (MOCHA) Moving Forward study seeks to determine the effectiveness of an innovative, community-driven program to improve the health and quality of life of low-income African-American men between the ages of 35 to 70 years by reducing identified social risk factors for chronic disease for these men. The project uses digital storytelling (DST) to encourage African-American men to tell their stories, especially related to stress, gender role stereotypes, and mental and physical health and well-being.